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  Schizophrenia associated genesUSPTO Application #: 20060088835Title: Schizophrenia associated genes Abstract: The present invention relates to the identification of genes which have been disrupted in patients diagnosed as suffering from schizophrenia and/or bi-polar affective disorder, as well as proteins encoded by the gene and antibodies thereto and to uses of such products as medicaments for treating schizophrenia and/or affective psychosis. The invention also relates to methods for diagnosing, patients suffering or predisposed to schizophrenia and/or affective psychosis, as well as screens for developing novel treatment regimes for schizophrenia and/or affective psychosis. (end of abstract)
Agent: Myers Bigel Sibley & Sajovec - Raleigh, NC, US Inventors: Benjamin Simon Pickard, Douglas Blackwood, David John Porteous, Walter John Muir, Ole Mors, Henrik Lykke Ewald USPTO Applicaton #: 20060088835 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060088835. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the identification of genes which have been disrupted in patients diagnosed as suffering from schizophrenia and/or bi-polar affective disorder, as well as proteins encoded by the gene and antibodies thereto and to uses of such products as medicaments for treating schizophrenia and/or affective psychosis. The invention also relates to methods for diagnosing patients suffering or predisposed to schizophrenia and/or affective psychosis, as well as screens for developing novel treatment regimes for schizophrenia and/or affective psychosis. [0002] Schizophrenia and Bipolar Affective Disorder are common and debilitating psychiatric disorders. Despite a wealth of information on the epidemiology, neuroanatomy and pharmacology of the illness, it is uncertain what molecular pathways are involved and how impairments in these affect brain development and neuronal function. Despite an estimated heritability of 60-80%, very little is known about the number or identity of genes involved in these psychoses. Although there has been recent progress in linkage and association studies, especially from genome-wide scans, these studies have yet to progress from the identification of susceptibility loci or candidate genes to the full characterisation of disease-causing genes (Berrettini, 2000). [0003] The cloning of breakpoints in patients with chromosome abnormalities (translocations, inversions etc.) has proved instrumental in the identification of many disease genes (e.g. Duchenne Muscular Dystrophy, Retinoblastoma, Wilm's Tumour, Familial Polyposis Coli, Fragile-X Syndrome, Polycystic Kidney Disease, many leukaemias and, very recently, a candidate speech and language disorder gene (Lai et al, 2001)). Such studies assume that the chromosomal breakpoints give rise to the clinical symptoms by either directly disrupting gene sequences or perturbing gene expression. In the same way that gene-trap mutagenesis can be used to identify disrupted mouse genes (Brennan & Skarnes, 1999), the physical "flag" created by a cytogenetic breakpoint provides a geographical pointer for the disease locus. [0004] It is amongst the objects of the present invention to provide genes and/or proteins postulated to be involved with the development and/or symptoms associated with schizophrenia and/or affective psychosis. [0005] As will be seen, the present invention is based on the molecular characterisation of a chromosomal disruption in subjects diagnosed as suffering from a schizophrenia and/or affective psychosis. A high-throughput Fluorescence in situ Hybridisation (FISH)-based approach has been adopted to map the chromosomal breakpoints in these patients. Consultation of the sequence data at the breakpoint locus not only allows efficient FISH probe selections to be made by the targeting of coding regions, but also proof of gene disruption can be made entirely by relating the exact position of probes to the genomic structure of a candidate gene. [0006] Four patients have been studied and their chromosomal disruptions characterised. Hereinafter the patients will be identified as patients 1-4. [0007] As will be seen, in one embodiment, the present invention is based on the molecular characterisation of a chromosomal rearrangement denoted t(3;8) (p13;p22) in a subject (patient 1) diagnosed as suffering from a schizoaffective disorder (see FIG. 1). A high-throughput Fluorescence in situ Hybridisation (FISH)-based approach was adopted to map the chromosomal breakpoints in these patients. Consultation of the sequence data at the breakpoint loci not only allowed efficient FISH probe selections to be made by the targeting of coding regions, but also proof of gene disruption was inferred entirely by relating the exact position of probes to the genomic structure of a candidate gene. [0008] One breakpoint (located on chromosome 8p22) in this subject lies near to a gene, N33, involved in the N-Linked Glycosylation pathway. [0009] This pathway consists of three stages. Firstly the assembly of a donor oligosaccharide at the endoplasmic reticulum lumen membrane. Secondly, the transfer of this molecule onto newly translated secretory and transmembrane proteins catalyzed by the oligosaccharyltransferase (OST) complex. Thirdly, there is subsequent modification of the oligosaccharides on the glycoprotein. N33 encodes a protein thought to be involved in the second stage of the pathway by analogy with yeast homologues. Without wishing to be bound by theory it is hypothesised that the breakpoint in the subject perturbs N33 expression indirectly through position effect silencing or separation of regulatory elements from the gene promoter (both effects have been shown to occur even when the breakpoints are up to 1 Mb from the target gene in some instances (Kleinjan et al 1999)). [0010] As the N33 gene is located within a chromosomal region repeatedly found positive in schizophrenia linkage studies the present inventors pursued this gene further by association study. [0011] Certain microsatellite repeat haplotypes have been identified at the N33 locus which are over-represented in schizophrenic patients and their families compared to the normal population. Subsequent sequencing of the N33 gene in haplotype carrying individuals is ongoing in order to identify causative mutations. [0012] The other breakpoint in this patient (3p13) has now also been fully characterised and demonstrated to disrupt a gene, SEMCAP3 (also known as KIAA1095). The present invention is therefore also based on a proposed role of this gene (normal and mutated forms) in the aetiology of schizophrenia and/or affective psychosis. [0013] In a further embodiment the present invention is based on the GRIK4 gene and observations of the present inventors of an involvement of this gene and/or protein with schizophrenia and/or affective psychosis. [0014] The GRIK4 gene is also known as KA1 and EAA1, but will herein be referred to as GRIK4 for simplicity, but should not be construed as limiting. [0015] The subject (patient 2) was one of a series of around 100 patients with comorbid schizophrenia and mild learning disability (US terminology: "mental retardation") who were screened using routine G-band karyotyping. This patient possesses a complex chromosomal rearrangement which can be described by standard nomenclature as; (46, XX, ins(8;11) (q13;q23.3q24.2)inv(2)(p12q32.1)t(2;11)(q21.3;q24.2)der (2) (2qter.fwdarw.2q32.1::2p12.fwdarw.2q21.3::11q24.2.fwdarw.11qter)der(11) (11pter.fwdarw.11q23.3::2q21.3.fwdarw.2q32.1::2p12.fwdarw.2pter)der(8) (8pter.fwdarw.8q13::11q23.2.fwdarw.11q24.2::8q13.fwdarw.8qter)). It has been repeatedly observed that schizophrenia occurs more frequently in individuals with mild learning disability than in the general population and recent work has revealed an increased heritability of this comorbid state. [0016] As described herein the FISH results reveal that the subject has a disruption in a brain expressed gene; namely, GRIK4 which is known to participate in molecular mechanisms responsible for modulating the strength of synaptic transmission. [0017] In a further embodiment the present invention is based on the characterisation of a balanced reciprocal translocation between chromosomes 9 and 14, t(9;14)(q34;q13) in a mother (patient 3) with schizophrenia and her daughter with schizophrenia co-morbid with mild learning disability. A brain transcription factor gene, NPAS3, is shown to be disrupted by the translocation at 14q13. Without wishing to be bound by theory, the present inventors hypothesis is that the disruption of this gene is responsible for the psychotic symptoms exhibited by the mother and daughter. [0018] As will be seen, the present invention is also based on the molecular characterisation of a chromosomal rearrangement denoted t(1;16)(p31.2;q21) (in patient 4). [0019] The proband met ICD-10 and DSM-IV criteria for definite schizophrenia. The translocation was inherited within other branches of the family with variable clinical expression. However some key translocation carriers of the subjects to whom the inventors had access had not passed the age of risk when clinically characterized. [0020] One breakpoint (located on chromosome 1p31.2) in patient 4 lies within an alternatively spliced form of the gene, PDE4B, involved in the attenuation of cAMP secondary messenger signaling. [0021] The remaining breakpoint in this patient (16q21) has now also fully characterised and demonstrated to disrupt a gene, CADHERIN 8 (CDH8). The present invention is therefore based in part on a proposed role of this gene in the aetiology of schizophrenia and/or affective psychosis. [0022] In a first aspect the present invention provides use of a polynucleotide fragment or fragments comprising SEMCAP3, N33, NPAS3, GRIK4, PDE4B and/or CDH8 gene(s) or a fragment(s), derivative(s) or homologue(s) thereof for the manufacture of a medicament for treating schizophrenia and/or affective psychosis in a subject. [0023] In another aspect the present invention provides use of a polypeptide fragment or fragments encoded by SEMCAP3, N33, NPAS3, GRIK4, PDE4B and/or CDH8 gene(s), or a fragment(s), derivative(s) or homologue(s) thereof for the manufacture of a medicament for treating schizophrenia and/or affective psychosis in a subject. [0024] Schizophrenia and/or affective psychosis as used herein relates to schizophrenia, as well as other affective psychoses such as those listed in "The ICD-10 Classification of Mental and Behavioural Disorders" World Health Organization, Geneva 1992. Categories F20 to F29 inclusive includes Schizophrenia, schizotypal and delusional disorders. Categories F30 to F39 inclusive are Mood (affective) disorders that include bipolar affective disorder and depressive disorder. Mental Retardation is coded F70 to F79 inclusive. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Association, Washington DC. 1994. Include all conditions coded 295.xx (Schizophrenia and Other Psychotic Disorders) and 296.xx (Major Depressive Disorders and Bipolar Disorders). Mental Retardation is coded 315, 317, 318 and 319. Continue reading... Full patent description for Schizophrenia associated genes Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Schizophrenia associated genes patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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